Dr. Alice Berger is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute and the Broad Institute. Her long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality and suffering by determining mechanisms of cancer development and identifying attractive therapeutic targets. To accomplish this goal, Dr. Berger uniquely leverages both genomics and cell biological methods to answer fundamental questions relating to cancer biology. Recently, Dr. Berger identified somatic mutations in the small GTPase gene, RIT1, in lung adenocarcinoma, one of the most prevalent and deadly cancer types in both men and women. The proposed research will test whether RIT1 mutations are required for tumor initiation and/or maintenance and will determine the critical effectors of RIT1 function in lung epithelial cells. The first aim will test the hypothesis that RIT1 is an initiating event in lung adenocarcinoma by generating a lung-specific, inducible mouse model of RIT1 mutation. To determine the mechanism of action of RIT1, the second aim will utilize unbiased quantitative proteomics and expression profiling to identify proteins/genes interacting with or regulated by RIT1 in lung epithelial cells. The third aim will determine genetic dependencies of RIT1-mutant cells using shRNA and CRISPR-mediated loss- of-function genetic experiments in tractable cellular models. Together, these studies will determine if RIT1 itself or any of its downstream effectors represent promising targets for therapeutic development in lung adenocarcinoma. The mentored phase of this award will involve establishment and analysis of in vivo and cellular models while the applicant simultaneously enhances her career development through focused biostatistics and leadership training. During the independent phase, candidate RIT1 effectors will be validated in vitro and in vivo, and the results used to apply for continued independent funding. The outstanding research environment and facilities available to Dr. Berger include laboratory space and full institutional access at both Dana-Farber Cancer Institute and the Broad Institute. Dr. Berger's research and training will be additionally enhanced by collaborations with established experts in mouse pathology, mouse modeling, and proteomics, as well as by mentoring from an advisory committee of leading cancer biologists including Dr. William Hahn, Dr. Todd Golub, Dr. Peter Hammerman, and Dr. Edward Harlow.